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Human mitochondrial transcription factor A (hmtTFA or Tfam), a 25-kDa protein encoded by a nuclear gene located on chromosome 10q21, is involved in the control of replication and transcription of mtDNA. To better understand the complex relationship between h-mtTFA and mitochondrial function, we assessed by western blot the levels of h-mtTFA in skeletal muscle from 7 patients affected by mitochondrial diseases (MD) caused by different mtDNA mutations. We related these results to exercise lactate production as well as to the pathologic features of the underlying myopathy. h-mtTFA levels were significantly inversely related to blood lactate and the percent of RRF, borderline to cox negative fibers. Our results indicate that hmtTFA may be involved in the cascade of events which determine functional impairment of MD. [ABSTRACT FROM AUTHOR]

Aims: To assess the impact of bariatric surgery on remission and relapse of type 2 diabetes mellitus (T2DM) at 10 years of follow-up and analyze predictive factors., Materials and Methods: Eighty-eight obese subjects undergoing Roux-en-Y gastric bypass (RYGB) and 25 subjects assigned to medical therapy (MT) were evaluated every year for 10 years. T2DM remission was defined by the American Diabetes Association criteria., Results: Body mass index (BMI), fasting glucose, and haemoglobin A1c (HbA1c) improved more markedly in RYGB than MT patients throughout the 10-year period. Post-surgery remission rates were 74% and 53% at 1 and 10 years, respectively, while remission did not occur in MT patients. One-year post-surgery, BMI decreased more in subjects with remission than in those without, but no further decrease was observed thereafter. By partial-least-squares analysis, T2DM duration, baseline HbA1c, and ensuing insulin therapy were the strongest predictors of remission. Remission was achieved at one year in 91% of patients with T2DM duration < 4 years, and 79% of them remained in remission at 10 years. On the contrary only 42% of patients with T2DM duration ≥ 4 years achieved remission, which was maintained only in 6% at the end of 10 years. By survival analysis, patients with T2DM duration < 4 years had higher remission rates than those with duration ≥ 4 years (hazards ratio (HR) 3.1 [95%CI 1.8-5.7]). Relapse did not occur before two years post-surgery and was much less frequent in patients with < 4- vs ≥ 4-year duration (HR 11.8 [4.9-29.4])., Conclusions: Short T2DM duration and good glycemic control before RYGB surgery were the best requisites for a long-lasting T2DM remission, whereas weight loss had no impact on the long-term relapse of T2DM., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Ball Milling technique has been used to prepare for the first time Vitis Vinifera extract-silica nanocomposites (VV-SiO 2 NCs), which combine the pharmacological effects of the extract with the effectiveness of silica as drug delivery system and active component in the treatment of wound healing. Different contents (1.0, 9.0 and 33.0 wt%) of Vitis Vinifera ethanolic extract were loaded into the silica matrix by grinding the extract with fumed silica using a planetary mill apparatus. The effect of the starting mixture composition and milling time on the final products was examined. The efficiency of the milling process was studied by X-ray Powder Diffraction, Nuclear Magnetic Resonance, and Infrared Spectroscopy, indicating that the natural extract was not affected by the increasing of the milling time. The successful loading of the extract was demonstrated by Nitrogen adsorption/desorption measurements, which showed a decrease in the SSA and pore volume of the silica with the increasing of the extract amount. Morphology of the nanocomposites, investigated by Scanning Electron Microscopy, showed an increased agglomeration in the nanocomposites with the increment of the VV extract amount. Studies on the total phenol quantification and antioxidant activity of the natural extract before and after incorporation in the silica matrix were also carried out. The obtained results indicate that the milling process does not alter the VV extract components, which result to be embedded in the silica matrix. An increase of the antioxidant activity with the increment of the extract amount in the nanocomposites, up to values comparable to the pure VV extract, was also observed., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To evaluate prognostic factors for canine acute pancreatitis (AP) based on clinical and laboratory data that can be easily assessed in veterinary practice., Design: Retrospective study between January 2010 and December 2013., Methods: The diagnosis of AP was based on clinical signs and an abnormal SNAP® cPL™ test result, concurrently with an ultrasound pattern suggestive of pancreatitis. Dogs were divided into survivors and non-survivors. We evaluated 12 clinical and laboratory parameters: respiratory rate, rectal temperature, white blood cells, haematocrit, total serum proteins, albumin, creatinine, cholesterol, total and ionised calcium, sodium and potassium. Clinical and clinicopathological data were statistically compared between survivors and non-survivors. A value of P < 0.05 was considered significant and P < 0.01 as highly significant. The odds ratio (OR) was calculated., Results: The study enrolled 50 client-owned dogs with a diagnosis of AP. Serum creatinine (P = 0.017) and sodium (P = 0.004) correlated significantly with the outcome. Serum sodium < 139.0 mmol/L (139.0 mEq/L) and serum creatinine > 212 μmol/L (2.4 mg/dL) were associated significantly with poor prognosis. Azotaemia (OR 12.5; 95% confidence interval (CI) 1.32-118.48) and hyponatraemia (OR 4.9; 95% CI 1.36-17.64) were associated with increased risk of death., Conclusions: In dogs with AP, hyponatraemia and azotaemia seem to be significantly associated with an increased risk of death., (© 2017 Australian Veterinary Association.)

In the present work new highly biocompatible nanovesicles were developed using polyanion sodium hyaluronate to form polymer immobilized vesicles, so called hyalurosomes. Curcumin, at high concentration was loaded into hyalurosomes and physico-chemical properties and in vitro/in vivo performances of the formulations were compared to those of liposomes having the same lipid and drug content. Vesicles were prepared by direct addition of dispersion containing the polysaccharide sodium hyaluronate and the polyphenol curcumin to a commercial mixture of soy phospholipids, thus avoiding the use of organic solvents. An extensive study was carried out on the physico-chemical features and properties of curcumin-loaded hyalurosomes and liposomes. Cryogenic transmission electron microscopy and small-angle X-ray scattering showed that vesicles were spherical, uni- or oligolamellar and small in size (112-220 nm). The in vitro percutaneous curcumin delivery studies on intact skin showed an improved ability of hyalurosomes to favour a fast drug deposition in the whole skin. Hyalurosomes as well as liposomes were biocompatible, protected in vitro human keratinocytes from oxidative stress damages and promoted tissue remodelling through cellular proliferation and migration. Moreover, in vivo tests underlined a good effectiveness of curcumin-loaded hyalurosomes to counteract 12-O-tetradecanoilphorbol (TPA)-produced inflammation and injuries, diminishing oedema formation, myeloperoxydase activity and providing an extensive skin reepithelization. Thanks to the one-step and environmentally-friendly preparation method, component biocompatibility and safety, good in vitro and in vivo performances, the hyalurosomes appear as promising nanocarriers for cosmetic and pharmaceutical applications., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: In large-scale clinical trials, the proliferation signal inhibitor (PSI) everolimus (EVL) combined with cyclosporine (CsA) and steroids, has been shown to be efficacious among de novo renal transplant recipients. Development of proteinuria has been shown to be an important predictor of renal dysfunction after conversion from CsA to a PSI-based regimen, and a key marker of allograft disease progression. Whether EVL de novo treatment is associated with a similar proteinuric effect is still under investigation., Methods: We compared the development of proteinuria among a cohort of 24 renal transplant recipients who were prescribed EVL (3 mg/d; n = 12; high-dose group) or 1.5 mg/d (n = 12; standard-dose group), in association with CsA, versus third control cohort of 12 patients who received mycophenolate mofetil (control group). EVL doses were adjusted to achieve trough blood levels of 3-8 ng/mL and 8-12 ng/mL among the standard and high-dose groups, respectively. We assessed renal function and protein excretion over a 2-year observation., Results: The high-dose group showed a trend toward greater proteinuria than the standard-dose on control groups. They showed significantly greater proteinuria from 9 months until 2 years; 0.86 +/- 0.5, 0.5 +/- 0.3, 0.47 +/- 0.2 g/24 h (P = .03 and P = .02, respectively, at 24 months). Mean proteinuria significantly correlated with mean EVL doses (n = .73; P = .0001). Concomitantly, the estimated glomerular filtration rate (eGFR) was significantly lower among patients treated with EVL 3.0 versus 1.5 mg/d (53.7 +/- 24 vs 73.04 +/- 17.6 mL/min; P = .037). Among patients in the standard-dose, the eGFR was consistently higher than the control group (62.6 +/- 29 mL/min)., Conclusion: EVL/CsA therapy is a safe alternative regimen for de novo renal transplant recipients. Higher EVL doses are correlated with greater increases in proteinuria. The standard EVL dose seems to be useful treatment strategy to prevent acute rejection episodes, with a better renal prognosis in the long term., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Background: Enteral feeding (tube feeding) is offered to many people with amyotrophic lateral sclerosis/motor neuron disease experiencing difficulty swallowing (dysphagia) and maintaining adequate nutritional intake leading to weight loss., Objectives: The aim of this review is to examine the efficacy of percutaneous endoscopic gastrostomy placement or other tube feeding placement on: (1) survival; (2) nutritional status; (3) quality of life. Another aim is to examine the minor and major complications of percutaneous endoscopic gastrostomy., Search Strategy: We searched the Cochrane Neuromuscular Disease Group Trials Register (June 2005), MEDLINE (from January 1966 to June 2005), and EMBASE (from January 1980 to June 2005) for randomized controlled trials. In addition we searched MEDLINE (January 1966 to June 2005) and EMBASE (January 1980 to June 2005) to identify non-randomized studies that might be worthy of review and discussion. We checked references in published articles, proceedings of scientific meetings, and enlisted personal communications to identify any additional references., Selection Criteria: All randomized and quasi-randomized controlled trials were to have been selected. Since no such trials were discovered, all prospective and retrospective controlled studies were reviewed in the 'Background' or 'Discussion' sections of the review., Data Collection and Analysis: We independently assessed study methodological design and extracted data. We considered the following outcomes: (1) survival rate in months (of primary interest), (2) nutritional status measured by weight change, change in body mass index, or other quantitative index of nutritional status, and (3) self-perceived quality of life We were also interested in reports of safety of the procedure as indicated by (4) minor and major complications of percutaneous endoscopic gastrostomy or other feeding tube placement., Main Results: We found no randomized controlled trials comparing the efficacy of enteral tube feeding with those people who continued to eat orally, without enteral feeding. We summarized the results of retrospective and prospective case controlled studies in the 'Discussion' section of this review., Authors' Conclusions: There are no randomized controlled trials to indicate whether enteral tube feeding is beneficial compared to continuation of oral feeding for survival. The 'best' evidence to date, based on controlled prospective cohort studies, suggests an advantage for survival in all people with amyotrophic lateral sclerosis/motor neuron disease, but these conclusions are tentative. Evidence for improved nutrition is also incomplete but tentatively favorable. Quality of life has only been addressed by a few researchers and needs more serious attention.

Patients with Alzheimer disease (AD) often exhibit psychotic symptoms associated with cognitive impairment. A few association studies have been carried out to determine if the serotonin transporter and receptor genes are potential risk factors for AD and/or associated psychopathology. The aim of this study was to investigate the association of a serotonin transporter gene-linked polymorphic region (5-HTTLPR) and the 5-HT2A receptor T102C polymorphism with the risk of developing dementia and/or psychotic symptoms in a group of sporadic AD patients from Italy. No significant differences in the distribution of allele and genotype frequencies of 5-HTTLPR and 5-HT2A T102C were found between patient and control groups. However, a significant association between the C102/C102 5-HT2A genotype and psychotic symptoms (p < 0.001) was observed. Our data strongly confirm results from previous studies suggesting that the C102 allele of the 5-HT2A receptor is associated with the occurrence of psychotic symptoms in AD. On the contrary, the serotonin transporter does not appear to be a major susceptibility factor in the pathophysiology of the disease.

Multiple sclerosis (MS) is one of the most common causes of neurological disability in early adulthood. The current literature is interested in identifying biological or DNA markers associated with genetic susceptibility to MS. The aim of this study is to investigate, by means of Bayesian statistical inference, whether the presence of Gc2 (Gc = group-specific component) and/or EsD1 (EsD = esterase D) alleles affects MS susceptibility. Gc and EsD are two classical genetic markers, being the first a serum protein polymorphism, the latter an isoenzyme polymorphism. The interest of the proposed statistical approach of searching for MS susceptibility genes relies on the analysis of two different functions, one function being inferred from our results on 56 unrelated patients from central Italy affected by MS, the other one from Italian and worldwide epidemiological data. The graphical analysis suggests that MS susceptibility is influenced by both Gc2 and EsD1 alleles; and EsD1 allele is more informative than Gc2. These results point out the advantages of the Bayesian approach in searching for susceptibility genes. Furthermore, the significant association between the considered alleles and the susceptibility to MS suggests possible hypotheses about the pathogenesis of the disease.

Steinert's myotonic dystrophy (DM) is a genetic autosomal dominant disease and the most frequent muscular dystrophy in adulthood. Although causative mutation is recognized as a CTG trinucleotide expansion on 19q13.3, pathogenic mechanisms of multisystem involvement of DM are still under debate. It has been suggested that mitochondrial abnormalities can occur in this disease and deficiency of coenzyme Q 10 (CoQ10) has been considered one possible cause for this. The aim of this investigation was to evaluate, in 35 DM patients, CoQ10 blood levels and relate them to the degree of CTG expansion as well as to the amount of lactate production in exercising muscle as indicator of mitochondrial dysfunction. CoQ10 concentrations appeared significantly reduced with respect to normal controls: 0.85 +/- 0.25 vs. 1.58 +/- 0.28 microg/ml (p < 0.05). Mean values of blood lactate were significantly higher in DM patients than controls (p < 0.05) both in resting conditions (2.9 +/- 0.55 vs. 1.44 +/- 1.11 mmol/L) and at the exercise peak (6.77 +/- 1.79 vs. 4.90 +/- 0.59 mmol/L), while exercise lactate threshold was anticipated (30-50% vs. 60-70% of the predicted normal maximal power output, p < 0.05). Statistical analysis showed that serum CoQ10 levels were significantly (p < 0.05) inversely correlated with both CTG expansion degree and lactate values at exercise lactate threshold level. Our data indicates the occurrence of reduced CoQ10 levels in DM, possibly related to disease pathogenic mechanisms associated with abnormal CTG trinucleotide amplification.

We report on a patient suffering from a progressive mitochondrial disorder characterized by ocular myopathy, exercise intolerance, and muscle wasting. Morphological examination of muscle biopsy showed increased variability in fiber size and scattered ragged-red fibers. Analysis of muscle mitochondrial DNA by Southern blot and PCR revealed a heteroplasmic single deletion of 4100 base pairs, located between nucleotide positions 8300 and 12,400. Western blot analysis showed high levels of the human mitochondrial transcription factor A (Tfam). Interestingly, we also detected an additional Tfam product, of approximately 22 kDa. This is the first case in which a qualitatively abnormal Tfam has been found to be associated with a mitochondrial disorder in humans.

Mexiletine is an antiarrhythmic drug that has been reported to exert antidystonic properties. We performed an open-label study to collect further evidence of the antidystonic effect of mexiletine in spasmodic torticollis (ST) and to evaluate its possible use in generalized dystonia. We administered mexiletine to six patients with dystonia (three with generalized dystonia and three with ST) who had failed to respond to previous pharmacotherapy. The drug was started at a dose of 200 mg/d by mouth and increased up to a maximum dose of 800 mg/d. Patients were evaluated at regular intervals over a 6-week period with use of the Fahn & Marsden Dystonia Scale and the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and videotaped. At the end of the trial, the videotapes were reviewed and scored by a blind observer. Patients were then followed for at least 1 year and evaluated every 3 months at the dose reached during the study period. No adverse effects were reported in five patients; in one patient, dizziness developed at the dosage of 800 mg/d, requiring a reduction of the dose. At the end of a 6-week period, a significant improvement in the rating scale for dystonia and in videotape ratings was observed after mexiletine treatment (p < 0.01). Our data indicate that mexiletine is a useful drug in dystonia treatment.

The aim of this study was to evaluate the effects of an aerobic training program on the metabolic and sympathetic responses to exercise in 12 patients with mitochondrial myopathies. A 10-week course of aerobic training, consisting of supervised exercise every other day on an electrically braked pedal-rate bicycle ergometer was prescribed to each patient and four healthy controls. Venous lactate, epinephrine (EP) and norepinephrine (NEP) levels were assessed at baseline and after the aerobic training by means of constant-workload exercise performed at near lactate threshold (LT). In patients, a decrease in exercise peak values, significant for lactate (-38.6%, P < 0.01) but not for catecholamines (EP: -26.0%, NEP: -22.1%) was observed after training, findings confirmed by the lactate/EP and lactate/NEP area ratios. The results show that lactate accumulation during exercise is decreased after aerobic training in mitochondrial myopathies and that the effect is partially dissociated from the catecholaminergic response. This in turn suggests that the lactate decrease can be explained, at least in part, by the improved muscle oxidative metabolism consequent to the proposed training program.

Transcranial magnetic stimulation (TMS) during a muscle contraction induces a motor-evoked potential (MEP) in the skeletal muscle followed by a cessation of EMG activity, the cortical silent period (C-SP). The C-SP is a useful parameter to indicate the activation of the motor system. Accurate determination of the C-SP can be important in amyotrophic lateral sclerosis (ALS), a progressive disorder of unknown etiology characterised by degeneration of upper and lower motor neurons. The aim of this study was to evaluate the sensitivity of C-SP as an index of motor system involvement, in ten patients affected by ALS, with a mean duration of the disease: 5. 5+/-3.4 months, by means of an objective computer-aided method to measure C-SP and its relationship to stimulation intensity. C-SP duration was significantly reduced in ALS patients compared to controls at low stimulation intensity corresponding to an MEP threshold increased by 15%. While in less severely affected patients C-SP duration approached control values at higher stimulation intensities (25 and 50% upper MEP threshold), in more severe ALS subjects it showed a further reduction, allowing them to be discriminated.

Sympathetic system activation is considered one of the main factors influencing lactate production during exercise in normal individuals. In order to assess the role of such activation in mitochondrial myopathies, we compared blood catecholamine levels to those of lactate during an intermittent exercise performed at workloads near anaerobic lactate threshold. Following an initial increment, the patients (n = 10) exhibited a steady-state blood lactate shifted right relative to controls (n = 7), the peaks being respectively 665 +/- 29% and 322 +/- 11% of baseline. Plasma catecholamine increase in mitochondrial myopathies was 272 +/- 21% for norepinephrine and 261 +/- 18% for epinephrine, not statistically different from controls. Lactate/norepinephrine and lactate/epinephrine area ratios were significantly higher in the subjects than in controls (2.36 versus 1.48 and 2.40 versus 1.57, respectively). The study shows that the abnormal lactate production in mitochondrial myopathies is independent of the catecholaminergic response at the transition from aerobic to anaerobic exercise.

The muscle changes occurring in Parkinson's disease (PD) may come about as a consequence of the modified pattern of motor unit activation and rigidity, which are characteristic of the disease. A tendency towards hypertrophy of type I fibers and, in some instances, atrophy of type II fibers has been observed. Fourteen patients affected by PD and 10 age-matched controls were studied in order to investigate these muscle changes. We indirectly evaluated muscle modifications by measuring muscle fiber conduction velocity (CV) and median frequency (MDF) of the power spectrum using automatic analysis of surface EMG. The tibialis anterior muscle was selected for the study of contractions electrically induced by 35 Hz pulse trains lasting 30 s; the myoelectric signal was detected using the 4-bar electrode technique described by Broman et al. (Broman, H., Bilotto, G. and De Luca, C.J. Myoelectric signal conduction velocity and spectral parameters: influence of force and time. J. Appl. Physiol., 1985, 58: 1428-1437). Muscle biopsy specimens were obtained in 4 PD patients by surgical excision at the site where the EMG recording electrode had been placed. The main difference observed between PD subjects and controls was the rate of change of MDF and CV during the course of stimulated contraction; patients with PD sustained a smaller fatigue related decrease in both parameters compared to controls. According to our histological data, this result can be explained by a type I fiber percentage which accounts for 79% of the myofiber population on average. As expected, the CV basal values correlated directly with type I fiber diameter. These data suggest that non-invasive surface EMG techniques are useful in assessing the modifications of muscle characteristics that are observed in PD patients and for analyzing some aspects of the peripheral fatigue in this disease.

Background: In this work we investigated whether serologically HLA class II compatible donor-recipient pairs showed differences in restriction fragment length patterns, and whether there is a correlation between the genomic differences observed and the incidence of rejection and acute graft versus host disease (GVHD)., Methods: High molecular weight DNA was extracted from thirty-three transplanted thalassemic patients and from their genotypically HLA identical donors. The DNA was digested with TaqI and PstI restriction enzymes, separated by horizontal electrophoresis and transferred onto nylon filters., Results: Differences at the molecular level were observed in only one patient, who rejected the transplant respect to his donor when DNA was digested with the TaqI restriction enzyme and hybridized with DPB cDNA probe., Conclusions: Although the molecular analysis revealed a difference between a patient who rejected the transplant and his donor, the RFLP typing confirmed the serological identity of the HLA class II antigens in all the other donor-recipient pairs studied.

The genomic DNA of 25 unrelated individuals with HLA haplotype A30 Cw5 B18 BfF1 DR3 D w52 DQw2 was digested with the restriction enzyme Taq I and hybridized with cDNA probes for C4 and 21-OH genes. Eighteen individuals and a non-Sardinian reference cell (DUCAF) were homozygous for the entire extended haplotype, six individuals were heterozygous for the HLA-A locus and homozygous for the rest of the same haplotype. All of the 18 homozygous individuals, four of the six heterozygous subjects and the DUCAF cell revealed the absence of two fragments at 3.2 and 2.4 kb corresponding to the 21-OH A gene, and the absence of fragments corresponding to the C4 B "long" or "short" gene. The contemporary absence of the 21-OH A and C4 B genes seems to be a constant characteristic of this extended haplotype in the Sardinian population and suggests that this and other extended haplotypes bearing C4 A or C4 B null alleles could be ancestral haplotypes which never duplicated at these loci.